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Article

Metal-Free Photoredox Catalyzed Cyclization of O-(2,4-Dinitrophenyl)oximes to Phenanthridines

by
Xiubin Liu
1,2,†,
Zhixing Qing
1,2,†,
Pi Cheng
1,2,*,
Xinyu Zheng
1,
Jianguo Zeng
1,2 and
Hongqi Xie
1,2,*
1
National and Provincial Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha 410128, China
2
Hunan Co-Innovation Center for Utilization of Botanicals Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work and should be considered joint first authors.
Molecules 2016, 21(12), 1690; https://doi.org/10.3390/molecules21121690
Submission received: 1 November 2016 / Revised: 25 November 2016 / Accepted: 6 December 2016 / Published: 8 December 2016
(This article belongs to the Section Photochemistry)
Browse Figures
Versions Notes

Abstract

:
A metal-free visible-light photoredox-catalyzed intermolecular cyclization reaction of O-2,4-dinitrophenyl oximes to phenanthridines was developed. In this study, the organic dye eosin Y and i-Pr2NEt were used as photocatalyst and terminal reductant, respectively. The oxime substrates were transformed into iminyl radical intermediates by single-electron reduction, which then underwent intermolecular homolytic aromatic substitution (HAS) reactions to give phenanthridine derivatives.

Graphical Abstract

1. Introduction

Phenanthridine is important substructure found in many naturally occurring alkaloids such as sanguinarine and chelerythrine [1,2,3]. Member of this family have demonstrated pharmaceutical activities, including antitumor [4], antifungal [5], antibacterial [6,7], DNA intercalator [8,9] and enzyme inhibition [10,11]. Furthermore, phenanthridine derivatives have wide applications in materials science because of their unique optoelectronic properties [12]. For the above reasons, diverse methodologies have been established to prepare phenanthridine derivatives, such as Lautens’s palladium-catalyzed domino direct arylation/N-arylation of triflates [13,14] and Studer’s tandem radical addition-cyclization reaction of 2-isocyanobiphenyls with diverse radical precursors [15,16,17,18].
The intramolecular homolytic aromatic substitution (HAS) reactions of iminyl radicals have shown advantages in the synthesis of phenanthridine derivatives and other N-containing heterocycles. One of the pathways to iminyl radicals is the N-O bond cleavage of O-acyl or aryl oximes under the UV or microwave irradiation at high temperature reported by Walton [19,20,21,22,23] and colleagues (Scheme 1A). Recently, s visible light photocatalytic strategy for the conversion of N-containing compounds though a N-radicals and radical ion intermediates pathway was proved to be a mild and general tool in radical reactions [24]. By taking advantage of the single-electron redox potential of a photoexcited catalyst Ir(ppy)3, Yu and co-workers [25,26] found that the acyl oximes could be converted to iminyl radical intermediates which were able to undergo intramolecular homolytic aromatic substitution to give phenanthridines (Scheme 1B). More recently, Leonori and co-workers developed a photoredox cyclization of iminyl [27] and amidyl radicals [28] derived from electron-poor aryloximes and aryloxy-amides, and this activation mode was applied in the synthesis of dihydropyrrole and lactam derivatives.
In the context of our study on biological active phenanthridine derivatives [11,29,30,31,32,33,34], we focused our attention on the development of facile, efficient and environmental-friendly synthetic method for phenanthridines and related compounds [35,36]. Drawing inspiration from the work of Walton, Yu and Leonori, we speculated that a visible-light photoredox catalyzed single electron reduction of electron-poor O-phenyl oximes 2 (Scheme 1C) to iminyl radicals might be followed by the generation of phenanthridines.

2. Results and Discussion

Among the commonly available electron-poor O-aryl oximes, O-(2,4-dinitrophenyl) oxime has the highest E1/2red potential value of −0.55 V [27], which is suitable for SET with the excited state of commonly used photocatalysts such as Ru(bpy)3Cl2.6H2O (E1/2*II/I = +0.77 V vs SCE), Ir(ppy)3 (E1/2*III/IV = −1.73 V vs. SCE) and the organic dye eosin Y (E1/2*EY/+EY = −1.11 V vs. SCE) [37]. In this study, as shown in Table 1, O-(2,4-dinitrophenyl) oxime (3a, Table 1) was used as model substrate. Ru(bpy)3Cl2·6H2O was firstly selected as photocatalyst and acetonitrile was used as solvent. After 24 h of reaction under visible light irradiation, only traces of phenanthridine (4a) could be detected along with the recovered starting compound 3a. The addition of the terminal reductant i-Pr2NEt was necessary to quench the visible light excited RuII* and give RuI species, a stronger electron donor (E1/2II/I = −1.33 V vs. SCE) [37] that could accelerate the single electron transfer (SET) process between the substrate and photocatalyst. As it can be seen in entry 2, target compound 4a was isolated in 32% yield when i-Pr2NEt was used. Next, DMSO (entry 3) and DMF (entry 4) were screened as reaction solvents, respectively, which demonstrated that DMF was suitable for this type of radical cyclization reaction. Further photocatalyst screening showed that the replacement of Ru(bpy)3Cl2.6H2O with Ir(ppy)3 (E1/2*III/IV = −1.73 V vs. SCE) [37] could afford phenanthridine 4a in 28% yield with part of starting material 3a being recovered (entry 5). As we anticipated, the combined use of i-Pr2NEt and Ir(ppy)3 significantly increased the yield of 4a to 51% (entry 6). It should be noted that 2-phenyl benzonitrile was detected as the major byproduct in entries 1–6. When the organic dye eosin Y (E1/2*EY/+EY = −1.11 V vs. SCE) [27] was used instead of Ir(ppy)3, an obviously increased yield of compound 4a was observed (75%, entry 7). The addition of i-Pr2NEt could give compound 4a in 74% yields after 12 h of reaction (entry 8). No conversion of substrate was observed when the reaction was carried out in darkness (entry 9). Interestingly, compound 4a was obtained in 8% yield when the reaction was carried out under visible light irradiation in the absence of photocatalyst (entry 10). According to Leonori’s studies [27], we suggested that a simple tertiary amine i-Pr2NEt would be able to reversibly interact with the 2,4-dinitrobenzene motif of 3a to give an electron donor–acceptor complex. Visible light irradiation could initiate a SET process of this complex to give the radical ion pair which would successively undergo fragmentation to give iminyl radical. Without visible light excitation, i-Pr2NEt could not initiate the cyclization reaction (entry 11). Finally, a trace of target compound 4a could be detected by simply heating a solvent of 3a in DMF at 100 °C for 6 h (entry 12). The generation of trace cyclization product in entry 12 was possibly ascribed to the intermolecular nucleophilic substitution because N-O bond in 3a was weak and the 2,4-dinitrophenoxy motif was a suitable leaving group in the substitution reaction.
Having developed a photoredox transition-metal-free radical cyclization as shown in Table 1, entry 8, we decided to explore the scope of substituent groups on the aryl ring of O-(2,4-dinitrophenyl)oximes 3. As shown in Table 2, when R1 were electron-donating groups such as methoxyl, methyl, 2,4-dimethyl and chloro atoms, the target compounds 4b–4e were isolated in moderate yields (46%–56%), which were lower than that of 4a. Interestingly, when group R1 was replaced by a trifluoromethyl group, an obviously increased yield of compound 4f was observed. It was suggested that electron-poor phenyl ring A of substrate 3 was much more suitable for the present HAS reaction. When the A ring of substrate 3 was 3-methyl)-substituted (compound 3g) the HAS reaction provided 4ga and 4gb in a ratio of 2:1 with total yield of 47%. Similar experimental results could be observed when ring A was 3,4-dimethoxyl-substituted (3h), and target compounds 4ha and 4hb were isolated in 58% total yield with a ratio of 2:1. We next turned to explore the scope of substituent group R2 on ring B of substrate 3. When R2 were 4′,5′-dimethoxy groups, target compounds 4i–4l were isolated in 40%–51% yield. Further exploration showed that changing R2 to 4-F (3m–3p) or 4-Me (3q–3r) had no apparent effects on the yield of the phenanthridine derivatives, and target compounds 4m–4r were isolated in 40%–57% yield.
It was worth noting that 2-phenylbenzonitrile derivatives 5 were detected as byproducts as shown in Scheme 2. We speculate that these nitriles were produced by a competing hydrogen atom transfer (HAT) process. In order to avoid the HAT process, O-2,4-dinitrophenyl acetophenone oximes 6 were evaluated as substrates in the radical cyclization reaction to give corresponding 6-methyl phenanthridines 7 (Table 3).
As shown in Table 3, the metal-free photoredox-catalyzed cyclization of O-2,4-dinitrophenyl acetophenone oximes 6 provided 6-methylphenanthridines 7 in excellent yield (85%–92%). Yields of target compounds 7a–7f were not obviously affected by the R1 group.
Based on the above experimental results in this study and previous work reported by Leonori [27], a reaction mechanism could be proposed, as shown in Scheme 3. In photocatalyst cycle I, visible light excited eosin Y* was reduced by i-Pr2NEt to eosin Y•−, which was a more powerful reductant that could reduce substrate 3 to radical anion A. The fragmentation of radical anion A led to phenoxyl anion B and iminyl radical intermediate C [27]. Cyclization of radical C through HAS process gave radical D which was further deprotonated by phenoxyl anion B to radical anion E. At this stage, radical anion E was involved in photocatalyst cycle II and was oxidized by excited eosin Y* to target compound 4 along with the generation of Eosin Y•− which was able to reduce substrate 3 and led to the generation of ground state eosin Y to complete photocatalyst cycle II.

3. Experimental Section

3.1. General Information

All reactions were carried out under a nitrogen atmosphere unless otherwise stated. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were obtained at 25 °C with CDCl3 as solvent and TMS as internal standard on a Bruker AVANCE III 400 M NMR instrument (Bruker, Swiss). HRMS data were obtained in the ESI mode on a 6530 Q-TOF/MS system (Agilent, Singapore). For flash chromatography silica gel (200–300 mesh) was employed (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China). The 1H-NMR and 13C-NMR spectrum of compounds 4 and 7 are available at the Supplementary Materials.

3.2. Representative Experimental Procedure for Visible Light Promoted Synthesis of Phenanthridines 4 and 7

A solution of O-(2,4-dinitrophenyl) oximes 3 or 6 (0.5 mmol), 1.5 eq of i-Pr2NEt, 2 mol % eosin Y in DMF (5 mL) was firstly bubbled with nitrogen for 10 min and then irradiated with a 25 W household compact fluorescent lamp. After 16 h of reaction, the resulting mixture was poured into water (50 mL) and then extracted with EtOAc (20 mL × 3). The combined organic solution was then washed with water (20 mL × 3). The organic layers were washed with brine and dried over MgSO4. The solvent were removed via vacuo and the residue was purified by flash column chromatography (SiO2) with petroleum ether/EtOAc (8:1) to give target compounds 4 or 7.

3.3. Physical, Analytical and Spectral Data

Phenanthridine (4a): White amorphous powder, 1H-NMR: δ ppm 9.28 (s, 1H), 8.58 (dd, J = 10.6, 8.4 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.90–7.80 (m, 1H), 7.78–7.72 (m, 1H), 7.68 (td, J = 8.1, 0.9 Hz, 2H).13C-NMR: δ ppm 153.7, 144.6, 132.7, 131.1, 130.3, 128.9, 128.8, 127.6, 127.2, 126.5, 124.2, 122.3, 122.0. HRMS (ESI+): calcd 180.0808 for C13H10N+ [M + H]+; found, 180.0810.
3-Methoxyphenanthridine (4b): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.24 (s, 1H), 8.49 (t, J = 8.4 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82–7.80 (m, 1H), 7.64–7.60 (m, 2H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 3.98 (s, 3H).13C-NMR: δ ppm 160.2, 154.1, 146.2, 132.9, 131.2, 128.9, 126.5, 125.7, 123.5, 121.5, 118.3, 118.2, 110.1, 55.7. HRMS (ESI+): calcd. 210.0913 for C14H12NO+ [M + H]+; found, 210.0918.
3-Methylphenanthridine (4c): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.28 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.87 (td, J = 1.6, 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.54 (dd, J = 1.6, 8.4 Hz, 1H), 2.63 (s, 3H). 13C-NMR: δ ppm 153.6, 144.6, 138.9, 132.7, 131.0, 129.6, 128.8, 128.7, 127.7, 126.2, 122.0, 121.7, 121.7 (overlapped), 21.6. HRMS (ESI+): calcd. 194.0964 for C14H12N+ [M + H]+; found, 194.0967.
2,4-Dimethylphenanthridine (4d): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.27 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.46 (s, 1H), 2.88 (s, 3H), 2.60 (s, 3H). 13C-NMR: δ ppm 151.3, 141.6, 137.3, 136.4, 132.6, 131.3, 130.5, 128.6, 127.1, 126.2, 123.8, 122.0, 119.7, 21.9, 18.6. HRMS (ESI+): calcd. 208.1121 for C15H14N+ [M + H]+; found, 208.1117.
3-Chorophenanthridine (4e): White amorphous powder, 1H-NMR: δ ppm 9.30 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.90 (td, J = 1.2, 7.2 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 2.4, 8.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H). 13C-NMR: δ ppm 154.7, 145.1, 134.3, 131.4, 130.1, 129.4, 129.0, 127.8, 127.7, 126.3, 123.6, 122.6, 121.8. HRMS (ESI+): calcd 214.0418 for C13H9ClN+ [M + H]+; found, 214.0414.
3-(Trifluoromethyl)phenanthridine (4f): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.38 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.96 (td, J = 1.6, 7.2 Hz, 1H), 7.90 (dd, J = 1.6, 8.8 Hz, 1H), 7.83 (td, J = 1.2, 8.0 Hz, 1H). 13C-NMR: δ ppm 154.9, 143.8, 131.8, 131.6, 130.5(q, 2JF-C = 32.5 Hz), 129.0, 128.7, 127.6 (q, 3JF-C = 4.2 Hz), 126.9, 126.4, 123.3 (q, 1JF-C = 276.0 Hz), 123.0 (q, 3JF-C = 3.2 Hz), 122.9, 122.2. HRMS (ESI+): calcd 248.06828 for C14H9F3N+ [M + H]+; found, 248.0682.
2-Methylphenanthridine (4ga): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.26 (s, 3H), 8.63 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.88 (td, J = 1.2, 7.2 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 2.67 (s, 3H). 13C-NMR: δ ppm 152.6, 142.8, 142.5, 137.0, 132.4, 130.8, 130.4, 130.4 (overlapped), 129.8, 128.7, 121.8, 121.8 (overlapped), 22.0. HRMS (ESI+): calcd 194.0964 for C14H12N+ [M + H]+; found, 194.0963.
4-Methylphenanthridine (4gb): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.34 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63–7.58 (m, 2H), 2.92 (s, 3H). 13C-NMR: δ ppm 152.2, 143.2, 137.8, 132.9, 130.8, 129.5, 128.7, 127.3, 126.7, 126.2, 124.0, 122.1, 120.1, 18.7. HRMS (ESI+): calcd 194.0964 for C14H12N+ [M + H]+; found, 194.0958.
2,3-Dimethoxylphenanthridine (4ha): White amorphous powder, 1H-NMR: δ ppm 9.17 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.60 (s, 1H), 4.12 (brs, 3H), 4.08 (brs, 3H). 13C-NMR: δ ppm 151.4, 150.9, 149.6, 140.6, 132.1, 130.5, 128.8, 126.4, 125.7, 121.3, 118.3, 110.0, 101.8, 56.1, 56.1 (overlapped). HRMS (ESI+): calcd 240.1019 for C15H14NO2+ [M + H]+; found, 240.1015.
3,4-Dimethoxylphenanthridine (4hb): White amorphous powder, 1H-NMR: δ ppm 9.33 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.85 (brt, J = 7.2 Hz, 1H), 7.68 (brt, J = 7.6 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 4.18 (s, 3H), 4.08 (s, 3H). 13C-NMR: δ ppm 153.8, 152.0, 144.6, 139.6, 132.8, 131.1, 128.9, 126.8, 125.5, 121.6, 119.3, 117.7, 113.9, 62.1, 56.7. HRMS (ESI+): calcd 240.1019 for C15H14NO2+ [M + H]+; found, 240.1020.
8,9-Dimethoxylphenanthridine (4i): White amorphous powder, 1H-NMR: δ ppm 9.14 (s, 1H), 8.43 (dd, J = 1.2, 8.4 Hz, 1H), 8.16 (dd, J = 0.8, 8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (td, J = 1.2, 7.2 Hz, 1H), 7.64 (td, J = 1.2, 7.2 Hz, 1H) 7.34 (s, 1H). 4.14 (s, 3H), 4.07 (s, 3H). 13C-NMR: δ ppm 152.9, 151.7, 150.0, 144.0, 130.1, 128.2, 127.8, 126.6, 123.8, 122.0, 121.7, 107.8, 101.8, 56.2, 56.1. HRMS (ESI+): calcd 240.1019 for C15H14NO2+ [M + H]+; found, 240.1016.
3,8,9-Trimethoxyphenanthridine (4j): White amorphous powder, 1H-NMR: δ ppm 9.10 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.56 (d, J = 2.4 Hz, 1H),7.31 (s, 1H), 7.29–7.27 (m, 1H), 4.13 (s, 3H), 4.06 (s, 3H), 3.99 (s, 3H). 13C-NMR: δ ppm 159.4, 153.1, 152.0, 149.3, 145.5, 128.6, 122.9, 120.8, 118.0, 117.9, 109.6, 107.7, 101.3, 56.1, 56.0, 55.5. HRMS (ESI+): calcd 270.1125 for C16H16NO3+ [M + H]+; found, 270.1127.
8,9-Dimethoxy-3-methylphenanthridine (4k): White amorphous powder, 1H-NMR: δ ppm 9.14 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 4.16 (s, 3H), 4.09 (s, 3H), 2.61 (s, 3H). 13C-NMR: δ ppm 152.9, 151.7, 149.7, 144.1, 137.9, 129.6, 128.8, 128.4, 128.3, 121.6, 121.5, 107.8, 101.7, 56.2, 56.1, 21.5. HRMS (ESI+): calcd 254.1176 for C16H16NO2+ [M + H]+; found, 254.1172.
3-Fluoro-8,9-dimethoxyphenanthridine (4l): White amorphous powder, 1H-NMR: δ ppm 9.17 (s, 1H), 8.44 (dd, J = 6.0, 8.8 Hz, 1H), 7.84 (s, 1H), 7.81 (dd, J = 2.8, 10.0 Hz, 1H), 7.45–7.40 (m, 1H), 7.38 (s, 1H), 4.16 (s, 3H), 4.09 (s, 3H). 13C-NMR: δ ppm 162.1 (d, 1JF-C = 245.8 Hz), 153.3, 152.9, 149.9, 145.2 (d, 3JF-C = 11.7 Hz), 128.2, 123.6 (d, 3JF-C = 9.4 Hz), 121.4, 120.6, 115.8 (d, 2JF-C = 23.8 Hz), 114.4 (d, 2JF-C = 20.4 Hz), 107.9, 101.6, 56.2, 56.1. HRMS (ESI+): calcd 258.0925 for C15H13FNO2+ [M + H]+; found, 258.0927.
9-Fluorophenanthridine (4m): Pale yellow amorphous powder, 1H-NMR: δ ppm 9.27 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.24–8.21 (m, 2H), 8.09 (dd, J = 6.0, 8.8 Hz, 1H), 7.81 (td, J = 1.6, 8.4 Hz, 1H), 7.72 (td, J = 1.2, 8.0 Hz, 1H), 7.47 (td, J = 2.4, 8.4 Hz, 1H). 13C-NMR: δ ppm 164.2 (d, 1JF-C = 251.0 Hz), 152.6, 144.5, 134.8 (d, 3JF-C =9.5 Hz), 131.5 (d, 3JF-C = 9.7 Hz), 130.2, 129.4, 127.2, 123.6, 123.4, 122.4, 116.8 (d, 2JF-C = 24.2 Hz), 107.2 (2JF-C = 22.5 Hz). HRMS (ESI+): calcd 198.0714 for C13H9FN+ [M + H]+; found, 198.0710.
3-Methoxy-9-fluorophenanthridine (4n): White amorphous powder, 1H-NMR: δ ppm 9.21 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.09–8.01 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.37–7.31 (m, 2H), 4.00 (s, 3H). 13C-NMR: δ ppm 164.4 (d, 1JF-C = 251.0 Hz), 1606, 152.9, 145.9, 135.0 (3JF-C = 8.9Hz), 131.7 (3JF-C = 9.8Hz), 123.6, 122.5, 118.3, 117.7, 115.8 (2JF-C = 24.2 Hz), 109.7, 106.5 (2JF-C = 22.5 Hz), 55.6. HRMS (ESI+): calcd 228.0819 for C14H11FNO+ [M + H]+; found, 228.0819.
9-Fluoro-3-methylphenanthridine (4o): White amorphous powder, 1H-NMR: δ ppm 9.23 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 2.0, 10.4 Hz, 1H), 8.05 (dd, J = 8.4, 6.0 Hz, 1H), 8.00 (s, 1H), 7.54 (dd, J = 1.2, 8.0 Hz, 1H), 7.44 (dd, J = 2.4, 8.4 Hz, 1H), 2.63 (s, 3H). 13C-NMR: δ 164.2 (d, 1JF-C = 250.3 Hz), 152.6, 144.6, 139.7, 134.9, 131.5 (d, 3JF-C = 9.6 Hz), 129.7, 128.9, 123.1, 122.2, 121.3, 116.3 (d, 2JF-C = 241 Hz), 106.9 (d, 2JF-C = 22.1 Hz), 21.6. HRMS (ESI+): calcd 212.0870 for C14H11FN+ [M + H]+; found, 212.0859.
3,9-Difluorophenanthridine (4p): White amorphous powder, 1H-NMR: δ ppm 9.25 (s, 1H), 8.42 (dd, J = 5.6, 9.2 Hz, 1H), 8.12 (dd, J = 2.4, 10.4 Hz, 1H), 8.07 (dd, J = 5.6, 8.8 Hz, 1H), 7.84 (dd, J = 2.4, 9.2 Hz, 1H), 7.48–7.42 (m, 2H). 13C-NMR: δ ppm 164.4 (d, 1JF-C = 251.0 Hz), 163.0 (d, 1JF-C = 247.9 Hz), 153.8, 145.8 (d, 3JF-C = 11.9 Hz), 134.5 (d, 3JF-C = 9.5 Hz), 131.7 (d, 3JF-C = 10.2 Hz), 124.3 (d, 3JF-C = 9.5 Hz), 123.0, 120.3, 116.7 (d, 2JF-C = 24.2 Hz), 116.3 (d, 2JF-C = 23.8 Hz), 114.8 (d, 2JF-C = 20.6 Hz), 107.0 (d, 2JF-C = 22.4 Hz). HRMS (ESI+): calcd 216.0619 for C13H8F2N+ [M + H]+; found, 216.0617.
9-Methylphenanthridine (4q): Pale yellow amorphous powder, 1H-NMR): δ ppm 9.26 (s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.76 (td, J = 1.2, 8.0 Hz, 1H), 7.69 (td, J = 1.2, 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 2.68 (s, 3H). 13C-NMR: δ ppm 153.3, 144.6, 141.6, 132.7, 130.0, 129.3, 128.7, 128.6, 126.8, 124.6, 124.0, 122.2, 121.5, 22.5. HRMS (ESI+): calcd 194.0964 for C14H12N+ [M + H]+; found, 194.0969.
3-Methoxy-9-methylphenanthridine (4r): White amorphous powder, 1H-NMR: δ ppm 9.21 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.30 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 2.4, 8.8 Hz, 1H), 4.01 (s, 3H), 2.65 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ ppm 160.0, 153.6, 146.2, 141.6, 133.0, 128.7, 128.2, 123.8, 123.4, 121.0, 118.0, 117.9, 109.8, 55.6, 22.5. HRMS (ESI+): calcd 224.1070 for C15H14NO+ [M + H]+; found, 224.1066.
1-Methylphenanthridine (7a): White amorphous powder, 1H-NMR: δ ppm 8.59 (d, J = 8.3 Hz, 1H), 8.51 (dd, J = 8.2, 1.2 Hz, 1H), 8.19 (dd, J = 8.2, 0.6 Hz, 1H), 8.10 (dd, J = 8.2, 1.0 Hz, 1H), 7.81 (dd, J = 8.2, 7.2 Hz, 1H), 7.73–7.64 (m, 2H), 7.60 (dd, J = 8.2, 7.2 Hz, 1H), 3.03 (s, 3H). 13C-NMR: δ ppm 158.9, 143.6, 132.6, 130.5, 129.3, 128.7, 127.3, 126.6, 126.4, 125.90, 123.8, 122.3, 122.0, 23.4. HRMS (ESI+): calcd 194.0964 for C14H12N+ [M + H]+; found, 194.09604.
3,6-Dimethylphenanthridine (7b): White amorphous powder, 1H-NMR: δ ppm 8.54 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 0.8, 8.4 Hz, 1H), 7.91 (s, 1H), 7.79 (td, J = 1.6, 8.0 Hz, 1H), 7.63 (td, J = 1.2, 8.0 Hz, 1H), 7.43 (dd, J = 1.6, 8.4 Hz, 1H), 3.02 (s, 3H), 2.59 (s, 3H). 13C-NMR: δ ppm 158.8, 143.8, 138.7, 132.6, 130.4, 129.0, 128.0, 126.8, 126.5, 125.6, 122.1, 121.7, 121.4, 23.3, 21.6. HRMS (ESI+): calcd 208.1121 for C15H14N+ [M + H]+; found, 208.1124.
3-Methoxy-6-methylphenanthridine (7c): Pale yellow amorphous powder, 1H-NMR: δ ppm 8.44 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.13 (dd, J = 0.4, 8.0 Hz, 1H), 7.75 (brt, J = 8.4 Hz, 1H), 7.56 (td, J = 0.8, 8.0 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.22 (dd, J = 2.4, 8.8 Hz, 1H), 3.97 (s, 3H), 3.00 (s, 3H). 13C-NMR: δ ppm 160.1, 159.3, 145.2, 132.7, 130.5, 126.5, 126.1, 124.9, 123.1, 121.8, 117.7, 117.2, 109.3, 55.5, 23.2. HRMS (ESI+): calcd 224.1070 for C15H14NO+ [M + H]+; found, 224.1066.
3-Fluoro-6-methylphenanthridine (7d): White amorphous powder, 1H-NMR: δ ppm 8.30 (d, J = 8.4 Hz, 1H), 8.48 (dd, J = 7.0, 8.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.83 (td, J = 8.0, 0.8 Hz, 1H), 7.74 (dd, J = 10.0, 2.8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.36 (td, J = 2.8, 8.8 Hz, 1H), 3.03 (s, 3H). 13C-NMR: δ ppm 162.8 (d, 1JF-C = 246.1 Hz), 160.5, 145.1(d, 3JF-C = 11.6 Hz), 132.5, 131.0, 127.3, 126.8, 125.6, 124.0 (d, 3JF-C = 5.0 Hz), 122.2, 120.6, 115.4 (d, 2JF-C = 23.8 Hz), 114.1 (d, 2JF-C = 20.3 Hz), 23.5. HRMS (ESI+): calcd 212.0870 for C14H11FN+ [M + H]+; found, 212.0877.
3-Chloro-6-methylphenanthridine (7e): White amorphous powder, 1H-NMR: δ ppm 8.52 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (td, J = 8.0, 1.2 Hz, 1H), 7.70 (td, J = 8.0, 1.2 Hz, 1H), 7.54 (dd, J = 8.8, 2.4 Hz, 1H), 3.01 (s, 3H). 13C-NMR: δ ppm 160.4, 144.5, 134.3, 132.2, 131.0, 128.8, 127.7, 127.0, 126.8, 126.0, 123.4, 122.4, 122.4, 23.5. HRMS (ESI+): calcd 228.0575 for C14H11ClN+ [M + H]+; found, 228.0570.
6-Methyl-3-(trifluoromethyl)phenanthridine (7f): Pale yellow amorphous powder, 1H-NMR: δ ppm 8.49 (brd, J = 7.2 Hz, 2H), 8.34 (brs, 1H), 8.17–8.16 (m, 1H), 7.82 (brd, J = 7.2 Hz, 1H), 7.73 (brs, 2H), 3.00 (brs, 3H). 13C-NMR: δ ppm 160.4, 142.9, 131.5, 130.9, 130.4, 130.1, 128.4, 126.8, 126.7, 126.5, 126.1 (q 1JF-C = 257.0 Hz), 122.8, 122.5, 122.0, 23.3. HRMS (ESI+): calcd 262.0838 for C15H11F3N+ [M + H]+; found, 262.0847.

4. Conclusions

In summary, a metal-free visible-light photoredox catalyzed intermolecular cyclization reaction of O-2,4-dinitrophenyl oximes to phenanthridines was developed in this study. Compared with Ru or Ir complexes, the organic dye type photocatalyst eosin Y used in this research is much cheaper. Furthermore, the reaction conditions for cyclization of O-2,4-dinitrophenyl oximes in this study were simple, mild and environmentally-friendly. Future studies will focus on applying this method to the synthesis other N-containing heterocycles based on tandem radical reactions.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/21/12/1690/s1.

Acknowledgments

This research was financially supported by National Natural Science Foundation of China (No. 31402109), Scientific Research Fund of Hunan Provincial Education Department (No. 14C0564) and Postgraduate Research and Innovation Project of Hunan Province (CX2014B302).

Author Contributions

Xiubing Liu, Zhixing Qing and Xinyu Zheng have performed the experiments and analyzed the data; Pi Cheng and Hongqi Xie have conceived the experiments and wrote the article; Jianguo Zeng has contributed to the reagents/materials/analysis tools.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 4 and 7 are available from the authors.
Molecules 21 01690 sch001 550
Scheme 1. Homolysis and one e− reduction of O-acyl and O-phenyl oximes to iminyl radicals.
Scheme 1. Homolysis and one e− reduction of O-acyl and O-phenyl oximes to iminyl radicals.
Molecules 21 01690 sch001
Molecules 21 01690 sch002 550
Scheme 2. Competitive transformation of iminyl radicals through HAS and HAT process.
Scheme 2. Competitive transformation of iminyl radicals through HAS and HAT process.
Molecules 21 01690 sch002
Molecules 21 01690 sch003 550
Scheme 3. Possible mechanism of visible-light promoted cyclization of O-phenyl oximes.
Scheme 3. Possible mechanism of visible-light promoted cyclization of O-phenyl oximes.
Molecules 21 01690 sch003
Table
Table 1. Optimization for the photoredox catalyzed intramolecular cyclization of 3a a.
Table 1. Optimization for the photoredox catalyzed intramolecular cyclization of 3a a.
Molecules 21 01690 i001
EntryPhotocatalystTerminal ReductantSolventYield of 4a b
1Ru(bpy)3Cl2·6H2O-MeCN6%
2Ru(bpy)3Cl2·6H2Oi-Pr2NEtMeCN32%
3Ru(bpy)3Cl2·6H2Oi-Pr2NEtDMSO37%
4Ru(bpy)3Cl2·6H2Oi-Pr2NEtDMF46%
5Ir(ppy)3-DMF28%
6Ir(ppy)3i-Pr2NEDMF51%
7eosin Y-DMF75%
8eosin Yi-Pr2NEtDMF74% c
9eosin Yi-Pr2NEtDMF0% d
10-i-Pr2NEtDMF7%
11-i-Pr2NEtDMF0% d
12--DMFtrace e
a Reaction conditions: 3a (0.2 mmol), photocatalyst (2 mol %), terminal reductant (3.0 equiv.), solvent (2.0 mL), 25 W compact fluorescent light bulb, under nitrogen atmosphere for 24 h; b Isolated yields; c 12 h reaction; d reaction was carried out in darkness; e 100 °C for 6 h.
Table
Table 2. Scope of substituent group on aryl ring of O-2,4-dinitrophenyl oximes 3 a.
Table 2. Scope of substituent group on aryl ring of O-2,4-dinitrophenyl oximes 3 a.
Molecules 21 01690 i002
SubstrateProductSubstrateProduct
Molecules 21 01690 i003 Molecules 21 01690 i004 Molecules 21 01690 i005 Molecules 21 01690 i006
3a4a 74%3b4b 51%
Molecules 21 01690 i007 Molecules 21 01690 i008 Molecules 21 01690 i009 Molecules 21 01690 i010
3c4c 46%3d4d 49%
Molecules 21 01690 i011 Molecules 21 01690 i012 Molecules 21 01690 i013 Molecules 21 01690 i014
3e4e 53%3f4f 80%
Molecules 21 01690 i015 Molecules 21 01690 i016 + Molecules 21 01690 i017 Molecules 21 01690 i018 Molecules 21 01690 i019 + Molecules 21 01690 i020
3g4ga 33% 4gb 17%3h4ha 38% 4hb 20%
Molecules 21 01690 i021 Molecules 21 01690 i022 Molecules 21 01690 i023 Molecules 21 01690 i024
3i4i 51%3j4j 46%
Molecules 21 01690 i025 Molecules 21 01690 i026 Molecules 21 01690 i027 Molecules 21 01690 i028
3k4k 40%3l4l 49%
Molecules 21 01690 i029 Molecules 21 01690 i030 Molecules 21 01690 i031 Molecules 21 01690 i032
3m4m 53%3n4n 46%
Molecules 21 01690 i033 Molecules 21 01690 i034 Molecules 21 01690 i035 Molecules 21 01690 i036
3o4o 43%3p4p 57%
Molecules 21 01690 i037 Molecules 21 01690 i038 Molecules 21 01690 i039 Molecules 21 01690 i040
3q4q 49%3r4r 43%
a Reaction conditions: 3 (0.5 mmol), photocatalyst (2 mol %), i-Pr2NEt (3.0 equiv.), solvent (5.0 mL), 25 W compact fluorescent light bulb, under nitrogen atmosphere for 12 h.
Table
Table 3. Cyclization of O-2,4-dinitrophenyl acetophenone oximes 6 to phenanthridines 7 a.
Table 3. Cyclization of O-2,4-dinitrophenyl acetophenone oximes 6 to phenanthridines 7 a.
Molecules 21 01690 i041
SubstrateProductSubstrateProduct
Molecules 21 01690 i042 Molecules 21 01690 i043 Molecules 21 01690 i044 Molecules 21 01690 i045
6a7a 92%6b7b 89%
Molecules 21 01690 i046 Molecules 21 01690 i047 Molecules 21 01690 i048 Molecules 21 01690 i049
6c7c 88%7d7d 91%
Molecules 21 01690 i050 Molecules 21 01690 i051 Molecules 21 01690 i052 Molecules 21 01690 i053
6e7e 85%6f7f 90%
a Reaction conditions: 3 (0.5 mmol), photocatalyst (2 mol %), i-Pr2NEt (3.0 equiv.), solvent (5.0 mL), 25 W compact fluorescent light bulb, under nitrogen atmosphere for 12 h.

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Liu, X.; Qing, Z.; Cheng, P.; Zheng, X.; Zeng, J.; Xie, H. Metal-Free Photoredox Catalyzed Cyclization of O-(2,4-Dinitrophenyl)oximes to Phenanthridines. Molecules 2016, 21, 1690. https://doi.org/10.3390/molecules21121690

AMA Style

Liu X, Qing Z, Cheng P, Zheng X, Zeng J, Xie H. Metal-Free Photoredox Catalyzed Cyclization of O-(2,4-Dinitrophenyl)oximes to Phenanthridines. Molecules. 2016; 21(12):1690. https://doi.org/10.3390/molecules21121690

Chicago/Turabian Style

Liu, Xiubin, Zhixing Qing, Pi Cheng, Xinyu Zheng, Jianguo Zeng, and Hongqi Xie. 2016. "Metal-Free Photoredox Catalyzed Cyclization of O-(2,4-Dinitrophenyl)oximes to Phenanthridines" Molecules 21, no. 12: 1690. https://doi.org/10.3390/molecules21121690

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